Neil Riordan

This study tested the chemical stability of intravenous ascorbic acid (vitamin C) in the form in which it is administered to patients for the management of cancer. It was found that the compound was still stable 6 hours after preparation – most infusions take place just 2 hours after preparation, which therefore makes them safe for patients.

Abstract

Context • Intravenous ascorbic acid (IVAA) has been used extensively as part of the management plan for cancer patients in various medical clinics throughout the United States. The current research team has evaluated its effectiveness in patients with cancer as part of an ongoing research program. However, no data are available that support the chemical stability of intravenously injectable ascorbic acid (AA) to ensure its safety and efficacy in that patient population. Its clinical use as well as its use in research conducted in US Food and Drug Administration-approved clinical trials require validation of its stability.

Objective • The study intended to evaluate the chemical stability of the compounded IVAA that it prepares.

Design • The research team conducted a stability analysis within a 6-h period, a period longer than the time required for most infusions, which typically take approximately 2 h. The study evaluated the stability of AA intravenous sets, which are compounded solutions for clinical or hospital use. The IVAA was prepared in sterile water, together with magnesium chloride (MgCl) and calcium gluconate (CaGluc) as buffers.

Setting • The study took place at the Marcus Institute of Integrative Health at Thomas Jefferson University (Philadelphia, PA, USA).

Outcome Measures • The study was performed for 2 dosages of an infusion set: 75 g and 100 g of IVAA. Interval testing included pH, particulate matter by light obscuration, and high-performance liquid chromatography assay. Analyses were performed at baseline and at 2-, 4-, and 6-h test intervals.

Results • The results demonstrated that IVAA remained highly stable throughout the 6-h period. It also passed the US Pharmacopeia’s criteria for pH and particulates when used with a 0.2 µ filter. Conclusions • These data suggest that IVAA, when prepared with sterile water, in addition to MgCl and CaGluc, is highly stable and safe to use in patients for up to 6 h after preparation.

This study investigated the effect of adding high-dose intravenous vitamin C to modulated electro-hyperthermia (mEHT), a treatment for cancer. Lung cancer patients received IV high-dose vitamin C in 3 groups: before, after and at the same time as mETH. Later-stage cancer patients were found to have lower plasma levels of vitamin C, and the group who received vitamin C and mETH simultaneously showed higher levels of vitamin C after treatment.

Abstract

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients.

Chronic kidney disease (CKD) patients often suffer from anemia, for which they must be treated with erythropoietin. This study treated 20 CKD patients with erythropoietin and intravenous high dose (500mg) vitamin C after every dialysis, and compared them to a control group (erythropoietin + intravenous iron). The group treated with vitamin C showed a significant increase in hemoglobin and a significant decrease in erythropoietin resistance index.

Evaluation of Effect of Ascorbic Acid on Ferritin and Erythropoietin Resistance in Patients of Chronic Kidney Disease.

Nand N, Deshmukh AR, Mittal R.

Abstract

OBJECTIVE:

This study was planned to evaluate the effect of short term intravenous ascorbic acid on reducing ferritin and erythropoietin resistance in patients of chronic kidney disease (CKD) on maintenance haemodialysis (MHD).

METHODS:

Forty adult patients [20 patients in group A with increased serum ferritin level (>500 ng/ml), transferrin saturation (TSAT) ≤20% and 20 patients in group B with normal serum ferritin level (<200 ng/ml), TSAT ≤20%] of end stage renal disease (ESRD) with erythropoietin hyporesponsiveness undergoing maintenance hemodialysis were included in the study. Group A was given intravenous (i.v.) ascorbic acid in a dose of 500 mg once a week after each 4 hours session of dialysis for 3 weeks in a month (total 1500 mg/month), for a period of 3 months along with erythropoietin 6000 IU subcutaneous (S/C) twice weekly without iron therapy. Group B was given erythropoietin (6000 IU S/C twice weekly after each hemodialysis) and intravenous (IV) iron 100 mg/week for 3 months. Hematological and renal investigations, erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (HsCRP), serum ferritin and TSAT were done at baseline and then one monthly intervals for three months whereas intact parathyroid hormone (iPTH) was measured at the start and end of the study.

RESULTS:

At the end of 3 months of study, in group A, Hemoglobin (Hb) and TSAT significantly increased while ferritin, HsCRP anderythropoietin resistance index (ERI) decreased significantly. In group B, the increase in Hb and TSAT were not significant statistically while ferritin increased significantly and fall in HsCRP and ERI were not significant statistically. The mean rise in Hb between subsequent months was higher in group A as compared to group B.

CONCLUSIONS:

Short term i.v ascorbic acid could be a new successful adjuvant in reducing ferritin and erythropoietin resistance and enhancing Hb and TSAT in CKD patients on MHD.

Acute respiratory distress syndrome (ARDS) is a serious condition where the inflamed lungs cannot supply enough oxygen to the body. This case report presents a rapidly deteriorating young woman with ARDS. She was treated with high dose (200 mg/kg per 24 h) intravenous vitamin C during her ICU stay in addition to veno-venous extracorporeal membrane oxygenation (ECMO) and antibiotics. The patient recovered well and did not develop post-ARDS fibroblasts.

Abstract

We report a case of virus-induced acute respiratory distress syndrome (ARDS) treated with parenteral vitamin C in a patient testing positive for enterovirus/rhinovirus on viral screening. This report outlines the first use of high dose intravenous vitamin C as an interventional therapy for ARDS, resulting from enterovirus/rhinovirus respiratory infection. From very significant preclinical research performed at Virginia Commonwealth University with vitamin C and with the very positive results of a previously performed phase I safety trial infusing high dose vitamin C intravenously into patients with severe sepsis, we reasoned that infusing identical dosing to a patient with ARDS from viral infection would be therapeutic. We report here the case of a 20-year-old, previously healthy, female who contracted respiratory enterovirus/rhinovirus infection that led to acute lung injury and rapidly to ARDS. She contracted the infection in central Italy while on an 8-d spring break from college. During a return flight to the United States, she developed increasing dyspnea and hypoxemia that rapidly developed into acute lung injury that led to ARDS. When support with mechanical ventilation failed, extracorporeal membrane oxygenation (ECMO) was initiated. Twelve hours following ECMO initiation, high dose intravenous vitamin C was begun. The patient’s recovery was rapid. ECMO and mechanical ventilation were discontinued by day-7 and the patient recovered with no long-term ARDS sequelae. Infusing high dose intravenous vitamin C into this patient with virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-ARDS fibroproliferative sequelae. Intravenous vitamin C as a treatment for ARDS may open a new era of therapy for ARDS from many causes.

Platelets are cells involved in blood clot formation to stop bleeding. This study investigated ex vivo whether platelet function was impacted after exposure to low-dose vitamin C and high-dose vitamin C. No detrimental effects to platelet function were reported during the first 5 days, but after 8 days there was a significant increase in the time to clot formation and in the speed of clot formation. The authors recommend caution when administering high dose vitamin C for longer than 8 days.

Impact of high dose vitamin C on platelet function.

Abstract

AIM: To examine the effect of high doses of vitamin C (VitC) on ex vivo human platelets (PLTs).

METHODS:

Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to: (1) normal saline (control); (2) 0.3 mmol/L VitC (Lo VitC); or (3) 3 mmol/L VitC (Hi VitC, final concentrations) and stored appropriately. The VitC additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of VitC used here correspond to plasma VitC levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography (TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate (ATP) secretion in response to collagen or adenosine diphosphate (ADP); and flow cytometry, for changes in expression of CD-31, CD41a, CD62p and CD63. In addition, PLT intracellular VitC content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time (PT), partial thrombplastin time (PTT), functional fibrinogen] and Lipidomics analysis (UPLC ESI-MS/MS).

RESULTS:

VitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L (Lo VitC) and 15.7 mmol/L (Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period (P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle (P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups (P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups (P > 0.05). Finally, VitC at the higher dose (3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid (P < 0.05).

CONCLUSION:

Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.

Sepsis occurs when an existing infection leads to an overwhelming immune response in the rest of the body, and can be potentially fatal. In this observational study in Virginia, 47 patients were treated with intravenous vitamin C, hydrocortisone and thiamine during their ICU stay. Their mortality rate (8%) was significantly lower (p<0.001) than that of the untreated group (40%), and their deaths were unrelated to sepsis. No patients in the treatment group of developed progressive organ failure.

Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.

Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J.

Abstract

BACKGROUND:

The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.

METHODS:

In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.

RESULTS:

There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001).

CONCLUSIONS:

Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

Herpes zoster, or “shingles”, is caused by reactivation of the varicella zoster virus (chickenpox). Intense pain and neuralgia are likely during episodes of shingles. This randomized control study administered intravenous vitamin C to herpes zoster patients in 3 doses (5g) over 5 days. Compared to the control group, the patients who received intravenous vitamin C had significantly lower pain scores in the 16 weeks of follow-up. Likewise, post-herpetic neuralgia occurred significantly less often in the group receiving intravenous vitamin C.

A Study of Intravenous Administration of Vitamin C in the Treatment of Acute Herpetic Pain and Postherpetic Neuralgia.

Kim MS, Kim DJ, Na CH, Shin BS.

Abstract

BACKGROUND:

Although there are several available management strategies for treatment of both acute pain of herpes zoster (HZ) and postherpetic neuralgia (PHN), it is difficult to treat them adequately.

OBJECTIVE:

The aim of this study was to evaluate the efficacy of intravenously administrated vitamin C on acute pain and its preventive effects on PHN in patients with HZ.

METHODS:

Between September 2011 and May 2013 eighty-seven patients who were admitted for HZ were assessed according to age, sex, underlying diseases, duration of pain and skin lesion, dermatomal distribution, and PHN. It was a randomized controlled study, in which 87 patients were randomly allocated into the ascorbic acid group and control group. Each patient received normal saline infusion with or without 5 g of ascorbic acid on days 1, 3, and 5 then answered questionnaires that included side effects and pain severity using visual analogue scale on days 1, 2, 3, 4, and 5. After discharge, the severity of pain was obtained at out-patient clinic or by telephone on weeks 2, 4, 8, and 16.

RESULTS:

There was no differences in severity of pain on patients’ age, sex, underlying diseases, duration of pain and skin lesion and dermatomal distribution between two groups (p>0.05). Since 8th week, pain score in ascorbic acid treatment group was significantly lower than control group (p <0.05). The incidence of PHN was significantly lower in the treatment group compared to control group (p=0.014). The changes of overall pain score was significantly different between the two groups (p<0.05).

CONCLUSION:

Intravenously administered ascorbic acid did not relieve acute HZ pain; but is effective for reducing the incidence of PHN.

Over the course of three months, 30 children with end-stage renal disease (ESRD) received intravenous vitamin C, and were compared with 30 children receiving placebo. Children who received vitamin C showed significantly lower levels of serum uric acid, cholesterol, low-density lipoproteins, and triglyceride. Complications of ESRD, including cardiovascular disease, could be prevented with this supplementation strategy.

Effect of vitamin C supplementation on lipid profile, serum uric acid, and ascorbic acid in children on hemodialysis.

El Mashad GM, ElSayed HM, Nosair NA.

Abstract

Children with end-stage renal disease (ESRD) suffer from dyslipidemia and hyperuricemia that might play a causal role in the progression of cardiovascular disease (CVD). The aim of the study is to assess the effects of Vitamin C supplementation on uric acid, ascorbic acid, and serum lipid levels among children on hemodialysis (HD). This prospective study was conducted in the pediatric nephrology unit at Menoufia University Hospital. The study included a total of 60 children with ESRD on maintenance HD therapy. They were divided into two groups: Group I (supplemented group, n = 30) received intravenous Vitamin C supplementation and Group II (control, n = 30) received placebo (intravenous saline) for three months. The results are shown as a mean ± standard deviation. Statistical evaluation was performed by SPSS software (version 11.5) using paired t-test. After supplementation with Vitamin C, the serum Vitamin C and high-density lipoprotein levels increased significantly with a significant reduction in the levels of serum uric acid, cholesterol, low-density lipoproteins, and triglyceride at the end of the study period. No significant changes were observed in the control group. Vitamin C can serve as a useful urate lowering medicine in HD patients to avoid complications of hyperuricemia. Furthermore, it had favorable effects on the lipid profile. This improvement can be considered as a preventive strategy in the progression of CVD in HD patients. Vitamin C supplementation improves ascorbic acid deficiency in these patients.

This research group from Virginia presents a case report of a patient with recurrent sepsis-associated acute respiratory distress syndrome (ARDS). The patient received intravenous vitamin C (50 mg/kg every 6 hours) during two separate hospitalizations along with standard care – their condition improved shortly thereafter. This group already reported a Phase I trial of intravenous vitamin C for sepsis patients with promising results.

Abstract

This case report summarizes the first use of intravenous vitamin C employed as an adjunctive interventional agent in the therapy of recurrent acute respiratory distress syndrome (ARDS). The two episodes of ARDS occurred in a young female patient with Cronkhite-Canada syndrome, a rare, sporadically occurring, noninherited disorder that is characterized by extensive gastrointestinal polyposis and malabsorption. Prior to the episodes of sepsis, the patient was receiving nutrition via chronic hyperalimentation administered through a long-standing central venous catheter. The patient became recurrently septic with Gram positive cocci which led to two instances of ARDS. This report describes the broad-based general critical care of a septic patient with acute respiratory failure that includes fluid resuscitation, broad-spectrum antibiotics, and vasopressor support. Intravenous vitamin C infused at 50 mg per kilogram body weight every 6 hours for 96 hours was incorporated as an adjunctive agent in the care of this patient. Vitamin C when used as a parenteral agent in high doses acts “pleiotropically” to attenuate proinflammatory mediator expression, to improve alveolar fluid clearance, and to act as an antioxidant.

This research team from Korea studied the effect of intravenous high-dose vitamin C for pain management and pain reduction. Twenty-four hours after a laparoscopic colectomy, patients who received vitamin C consumed significantly less morphine and had lower pain scores than those who received placebos.

Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after Laparoscopic Colectomy: A Randomized Controlled Trial.

Jeon Y, Park JS, Moon S, Yeo J.

Abstract

Background and Objective. Vitamin C has antioxidant, neuroprotective, and neuromodulating effects. Recently, it showed antinociceptive effect as a result of the antioxidant properties. Therefore, we designed this study to assess the effect of intravenous vitamin C on opiate consumption and pain in patients undergoing laparoscopic colectomy. Methods. A total of 100 patients were enrolled and allocated to receive 50 mg/kg vitamin C or placebo by intravenous infusion immediately after induction of anesthesia. Morphine consumption and scores of pain were assessed at 2, 6, and 24 h after completion of surgery. Results. There were 97 patients included in the analysis. Patients who received vitamin C had higher plasma concentrations of vitamin C at the end of surgery, significantly lower morphine consumption at the 2 h after end of surgery, and significantly lower pain scores at rest during first 24 h postoperatively. There was no significant difference between groups in side effects, fatigue score, or pain score during cough. Conclusion. This study shows high dose vitamin C infusion decreased postoperative pain during the first 24 h and reduced morphine consumption in the early postoperative period. Additional research needed to examine whether higher doses of vitamin C and longer infusion times can amplify these effects.